In vitro bactericidal and in vivo therapeutic activities of a new rifamycin derivative, KRM-1648, against Mycobacterium tuberculosis

Abstract

The in vitro and in vivo activities of a new rifamycin derivative, KRM-1648, against Mycobacterium tuberculosis H37Rv were compared with those of rifampin. Bactericidal activity was evaluated by using a silicone-coated slide culture method. The MBC of KRM-1648 was 0.15 to 0.3 microgram/ml for 24 h of exposure, while that of rifampin was > 160 microgram/ml under the same conditions. Against experimental murine tuberculosis, KRM-1648 exhibited significant therapeutic effects, in terms of prolonged survival times for mice compared with those with rifampin treatment, even at lower doses, such as 1 and 3 mg/kg. At a dose of 3 mg/kg, KRM-1648 was at least as effective as rifampin at 10 mg/kg. The combination of KRM-1648 (3 mg/kg) plus isoniazid (3 mg/kg) plus ethambutol (10 mg/kg) exhibited much more activity than did rifampin (10 mg/kg) plus isoniazid (3 mg/kg) plus ethambutol (10 mg/kg). These findings suggest that KRM-1648 is a promising candidate for the treatment of tuberculosis.

Antibacterial activity of rifamycins for M. smegmatis with comparison of oxidation and binding to tear lipocalin

“…Similar results have been published for rifalazil against Mycobacterium tuberculosis H37Rv (MICs ranging from 0.004 to 0.035 μg/ml) [40, 41]. Mycobacterium smegmatis appears to be a valid model for comparison.…”

Antimicrobial agent resistance in mycobacteria: molecular genetic insights.

“…Although there is only limited clinical experience in treating RIF-resistant M. tuberculosis with rifabutin (49,61,126), these data suggest that patients with strains containing certain rpoB mutations may be amenable to rifabutin therapy. There remains a need for molecular genetic studies to directly probe the exact relationship between rpoB mutations and resistance to rifabutin, rifapentine, and other new rifamycin derivatives (177,178).…”

Pharmacokinetics of KRM-1648, a new benzoxazinorifamycin, in rats and dogs

“…These metabolites exhibited pharmacokinetic properties such as tissue tropism (in rats) and long t 1/2 s (in dogs) similar to those of the parent compound. Given these findings and the fact that the in vitro microbiological activities of these metabolites are roughly comparable to that of the parent compound in both potency and bacterial spectrum (10), it appears likely that these metabolites contribute to the excellent in vivo effect of KRM-1648 (5,13,14,16,27,33,34).…”

“…KRM-1648 [3Ј-hydroxy-5Ј-(4-isobutyl-1-piperazinyl)benzoxazinorifamycin] is a new rifamycin derivative which appears to be highly suitable for use in humans since its activity is superior to those of rifampin and rifabutin against M. avium complex and Mycobacterium tuberculosis in various experimental models in vitro (11,20,23,32) and in vivo (5,13,14,16,27,33,34).…”